程序性细胞死亡配体 2 (PD-L2) 是受体程序性细胞死亡 1 (PD-1) 的配体，与其孪生配体 PD-L1 的同一性为 34%，与 PD-1 的结合亲和力高于 PD -L1。然而，PD-L2 在非小细胞肺癌 (NSCLC) 进展，特别是烟草诱发的癌症进展中的作用尚未完全了解。在这里，我们发现 PD-L2 通过招募调节性 T 细胞 (Treg) 来促进小鼠模型中的肿瘤生长。在 NSCLC 患者中，肿瘤样本中的 PD-L2 表达水平高于对应的正常对照，并且与患者对抗 PD-1 治疗的反应呈正相关。机制上，PD-L2结合癌细胞上的受体排斥引导分子B（RGMB）并激活细胞外信号调节激酶（Erk）和核因子κB（NFκB），导致趋化因子CCL20的产生增加，从而招募Tregs并促进非小细胞肺癌进展。一致地，RGMB 或 NFκB p65 的敲低抑制了 PD-L2 诱导的 CCL20 产生，而 PD-L2 的沉默抑制了 NSCLC 细胞的 Treg 募集。此外，香烟烟雾和致癌物质苯并（a）芘（BaP）通过芳烃受体（AhR）介导的转录激活上调肺上皮细胞中的PD-L2，其缺陷显着抑制BaP诱导的PD-L2上调。这些结果表明 PD-L2 通过 RGMB/NFκB/CCL20 级联介导烟草诱导的 Tregs 募集，并且针对该途径可能在 NSCLC 中具有治疗潜力。© 2024。作者。

Programmed cell death ligand 2 (PD-L2), a ligand for the receptor programmed cell death 1 (PD-1), has an identity of 34% with its twin ligand PD-L1 and exhibits higher binding affinity with PD-1 than PD-L1. However, the role of PD-L2 in non-small cell lung cancer (NSCLC) progression, especially tobacco-induced cancer progression, has not been fully understood. Here, we found that PD-L2 promoted tumor growth in murine models with recruitment of regulatory T cells (Tregs). In patients with NSCLC, PD-L2 expression level in tumor samples was higher than in counterpart normal controls and was positively associated with patients' response to anti-PD-1 treatment. Mechanismly, PD-L2 bound its receptor Repulsive guidance molecule B (RGMB) on cancer cells and activated extracellular signal-regulated kinase (Erk) and nuclear factor κB (NFκB), leading to increased production of chemokine CCL20, which recruited Tregs and contributed to NSCLC progression. Consistently, knockdown of RGMB or NFκB p65 inhibited PD-L2-induced CCL20 production, and silencing of PD-L2 repressed Treg recruitment by NSCLC cells. Furthermore, cigarette smoke and carcinogen benzo(a)pyrene (BaP) upregulated PD-L2 in lung epithelial cells via aryl hydrocarbon receptor (AhR)-mediated transcription activation, whose deficiency markedly suppressed BaP-induced PD-L2 upregulation. These results suggest that PD-L2 mediates tobacco-induced recruitment of Tregs via the RGMB/NFκB/CCL20 cascade, and targeting this pathway might have therapeutic potentials in NSCLC.© 2024. The Author(s).